DESCRIPTION: A recently discovered mechanism of inflammatory injury, the "Poly (ADP-ribose) Synthetase (PARS) pathway", has been implicated in the pathogenesis of neuronal injury. Triggered by oxidant-induced DNA single stran breaks, PARS catalyzes an energy-consuming polymerization of ADP-ribose, resulting in NAD depletion, inhibition of glycolysis and mitochondrial respiration, and the ultimate reduction of intracellular high energy phosphates, which culminates in neuroinjury. The applicants have developed a novel class of compounds with neuroprotective potential. In this proposal, we present evidence that INH2BP, a potent non-toxic PARS inhibitor, reduces oxidant-induced cellular injury in vitro. Furthermore, we present evidence for the role of PARS and protective effect of INH2P in murine models of stroke and neuroinflammation. Inotek's long-term intention is to develop INH2BP as a drug for the treatment of neural injury associated with various forms of cerebral ischemia. The specific aims of the present proposal is to perform definitive i vivo studies in murine model of brain trauma in order to test whether INH2BP can reduce the degree of injury. PROPOSED COMMERCIAL APPLICATION: The lack of an effective treatment for brain trauma means that a successful agent will have a major proportion of a multi-million dollar market worldwide.